RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA.
CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
结果:我们的数据表明,MUT缺乏与严重的蛋白质组失调有关,揭示参与溶酶体和自噬功能的分子因子。为了阐明MUT缺陷对溶酶体和自噬调节的影响,我们分析了MMA溶酶体的形态和功能,显示出深度改变,从而证实了组学数据。MMA细胞的溶酶体表现为具有低降解能力的扩大的液泡。尽管如此,用抗丙酸药物治疗能够完全挽救MUT缺陷细胞中的溶酶体形态和功能活性。这些结果表明MUT缺乏与溶酶体-自噬功能障碍之间存在严格的联系,为MMA提供有希望的治疗前景。
结论:在MUT缺陷细胞中已经证明了自噬和溶酶体功能调节中存在缺陷的稳态机制。我们的数据证明MMA触发了影响自噬体-溶酶体融合和溶酶体活性的这种功能障碍。